The pancreas is an elongated organ which lies behind and below the stomach and above the first loop of the duodenum. It weighs approximately 100 grams and consists of both exocrine and endocrine tissues. The exocrine portion is divided into lobes by connective tissue septa, and each lobe is divided into several lobules. These lobules are composed of grape-like clusters of secretory cells which form sacs known as acini. An acinus is a functional unit, and all acini drain into interlobular ducts which merge to form the main pancreatic duct. It, in turn, joins together with the bile duct from the liver to form the common bile duct that empties into the duodenum. Pancreatic acinar cells make up more than 80% of the total volume of the pancreas and function in the secretion of the various enzymes which assist digestion in the gastrointestinal tract.
The endocrine portion of the pancreas consists of islands of tissues known as islets of Langerhans. These dispersed islets comprise approximately 2% of the total volume of the pancreas. The basic function of the pancreatic endocrine cells is to secrete certain hormones which participate in the metabolism of proteins, carbohydrates, and fats. The hormones secreted by the islets are insulin, glucagon, somatostatin and pancreatic polypeptide.
Carcinoma of the pancreas is the fourth commonest cancer causing death in the United States with an incidence in 1993 of 27,700 and a mortality of 24,500 (Caldas et al, (1994) Nature Gene 8:27-32). The disease is more common in males than females and the peak incidence is between the ages of 60 to 70. Incidence of carcinoma of the pancreas is 2 times greater in patients with diabetes mellitus and 2.0 to 2.5 times greater in smokers than non-smokers.
The median survival for individuals subject to pancreatic cancer is six months from the time of diagnosis. Approximately 10% of patients survive one year and the five year survival rate is 1 to 2 percent. (Harrison Principles of Internal Medicine 11th edition, Braunwald et al editors McGraw-Hill Book Co., New York, pg. 1381-1384.)
Recently, Schutte et al ((1995) Proc Natl Acad Sci 92:5950-5954) used the method of representational difference analysis (RDA) as described by (Lisitsyn et al (1995) Proc Natl Acad Sci 92:151-155) to demonstrate a homozygous deletion in pancreatic carcinoma mapping to a 1-cM region at 13ql.3. The deletion was flanked by the markers D135171 and D135260 and lay within the 6-cM region identified as containing the BRCA.sub.2 (600185) locus of heritable breast cancer susceptibility. Schufte supra suggest that the same gene maybe involved in multiple tumor types and that its function is that of a tumor suppressor rather than that of a dominant oncogene. Additionally, Muller-Pillasch et al. submitted to EMBL/Genbank/and the gene database of Japan (DDBJ DDBI) in 1994 a nucleotide sequence designated NCBI GI 533948 which was found to be differentially expressed in the pancreatic cancer cell line PATU.
The Sanger Genome Centre (Cambridge, UK) has been involved in a large-scale genomic DNA sequencing project in the region of human chromosome 13 (13q12) thought to contain the gene responsible for Breast Cancer Type 2 (BRCA2). They recently deposited several large fragments of this DNA sequence on their Web Server, in unfinished and unannotated form.
Current methods for the diagnosis of pancreatic cancer include measurement of serum anylase and lipase values, however these values are found to be abnormal in only 10% of all cases. Blood, urine and feces of individuals subject to carcinoma of the body and tail of the pancreas are often normal. Also, standard gastrointestinal x-rays may suggest the presence of carcinoma of the head of the pancreas, but only 50% of all patients with this type of carcinoma have an abnormal examination (Harrison's Principles of Internal Medicine supra).
In view of the difficulty in diagnosing pancreatic cancer, and the low survival rates of individuals subject to pancreatic cancer, it would be advantageous to have an early and accurate method for the detection of pancreatic cancer. It would also be advantageous to provide therapeutic compositions and methods for prevention and treatment of pancreatic cancer.